Recovery of procaine



Patented Oct. 30, 1951 RECOVERY OF PROCAIN E John Talbot McOombie, Walton-on-the-Hill, Paul Frederick Ernest Mann, London, and Anthony Musgrave Wild, Cheam, England, assignors to The Distillers Company Limited, Edinburgh, Scotland, a British company No Drawing.

Application June 15, 1950, Serial No. 168,376. In Great Britain July 1, 1949 6 Claims.

The present invention relates to an improved process for the recovery of procaine from aqueous solutions thereof.

Procaine is a trade name given to the compound beta diethylamino ethyl para aminobenzoate-hy-drochloride, also known under the names novocaine, ethocaine, kerocaine, syncaine and neocaine, and which compound is used as a local anaesthetic. Procaine penicillin which is the salt formed by the reaction of procaine and a salt of penicillin is a compound of considerable therapeutic value.

In the manufacture of procaine penicillin, and particularly in processes for the conversion of procaine penicillin to other salts of penicillin, as described in our copending United States application Ser. No. 133,944, dated December 19, 1949, large volumes of aqueous solutions containing small, 1. e. about 5% or less, amounts of procaine are obtained and the provision of a simple and efiicient process for the recovery of procaine from such solutions represents a substantial feature in the economical operation of these processes.

It is not expedient to recover the procaine from such solutions by simple evaporation since the aqueous penicillin solutions obtained in this way contain gummy, coloured and other impurities which would be associated with the procaine thus obtained, and moreover procaine itself is not very heat stable and by evaporation of large volumes of aqueous solutions thereof, even under reduced pressure a certain amount of decomposition will take place. In addition evaporation in this way under reduced pressure is a relatively costly process.

Accordingly, it is an object of the present invention to provide a simple and efiicient process for the recovery of procaine from dilute aqueous solutions thereof as obtained in processes for the manufacture of penicillin derivatives.

The method for the recovery of the procaine employed according to the present invention is to adjust the pH of the aqueous procaine-containing solution to a value greater than about 8 to precipitate the procaine in the form of its free base. As indicated above, the procaine solutions also contain undesirable impurities which would co-precipitate with the procaine base and, accordingly, therefore, the aqueous procaine solution is treated with a small amount of activated carbon to remove these impurities. It has been found, however, that by carbon treatment of the solution in this way a substantial amount-in some cases up to about 40% by weight of the a b i procaille P y. P w wed 19,- h 93%.

bon, and also that when washing the carbon with organic solvents to remove the adsorbed procaine, although satisfactory removal of the procaine is effected the impurities adsorbed on the carbon are also removed in this way. We have found that if the carbon is washed with a small amount of a dilute aqueous mineral acid of normality not greater than about 2, substantially all the procaine is removed without carrying with it any substantial amount of the gummy and other impurities adsorbed on the carbon.

According to the process of the present invention an aqueous procaine-containing solution at a pH less than about 8 is contacted with a small amount of activated carbon, the solution separated and the carbon washed with aqueous dilute acid of normality not greater than about 2, the filtrate and the washings obtained being adjusted to a pH greater than 8 and preferably between 10 and 12, thus precipitating the procaine in the form of the base beta-di-ethylaminoethyl--para-aminobenzoate.

The carbon treatment of the procaine solution is most suitably effected by agitating with the solution activated carbon in amount of the order of about 1% by weight of the solution, suitably for a period of to 1 hour, the pH of said solution being less than about 8, filtering off the carbon which will retain much of the gummy, colcured and other impurities associated in the solution with the procaine and thereafter washing the filter cake of carbon with a small amount of a dilute aqueous mineral acid of normality not greater thanabout 2. This carbon treatment can also be efiected by passing the aqueous procaine-containing solution through a static mass of activated carbon, suitably contained in a column.

The mineral acids which it is preferred to employ for washing the activated carbon include hydrochloric acid and sulphuric acid. It should be noted that the use of phosphoric acid should be avoided as this may result in the precipitation of phosphate salts during the subsequent precipitation of the procaine base, unless the final pH of the solution is not in excess of 10-105 and the temperature is maintained at or below room temperature.

The precipitation of the procaine from the purified aqueous solution, in the form of the corresponding base, by adjusting the pH to a value greater than 8, and preferably between 10 and 12, is very suitably effected by the addition of aqueous sodium hydroxide, although it should; ans ih toth a k a nts ma a so he:

present invention whereby improved re'sfilt'sfir'iay be obtained the aqueousz procairie containingi solution is extracted with a substantiallwim miscible organic solvent suerirasamyii eetate; butyl acetate, chlorofrm,- ethef 'n'd the -like, after adjustment of the pH of the solution toa value greater than 8, and preferablyfbetween lfl and 12, the organic solvent extraetbein'gtsepa rated and then re-extracted with water at a pH of less than 6 and preferably about 2, theaqiieo'us extract obtained being separated and the pH thereof adjustedto =-a'-- value greater than 8 and preferably between and' l'Z'; thus-precipitating the p'rocaine base.

' It has been found that when l employing" this" modification of the invention the" procaine i is purer form; and advantagesobtained that con centration of the procaine c'ontaining solution is obtained, with consequent reduction the volume of solution being treated and also the extraction steps ensure the removal-ofrnir'reral and other salts which may be asso'ciated with theproca-ine and whiclimight otherwise be-pre-' cipitated with the procaine base: This extrac-* ,tiontreatment may talie placebeioremr after recovered in slightly greater yields and in a the "carbon treatmentof the procaine' contairiing solution.

The following "examples are given to illustrate the process of "the-present invention; The-parts"- by weight and pa'rtsby'volur'ne bear the-sa merelation to each" other as do grams tomillilitr's.

Example 1:

5oo lparts y volume of an aqueous solutionof a; pH-bfT-Sf obtained "in'the process for the'con'f f versiorroi procaine penicillin tosodiu'm penicillin as described in our copending United states ap' plication Ser. No. 133,944, dated December 19; 1949, containing 9.7 5 parts-by weightofprocaine, are treated with l by weight of 1 activated car bon with agitation and the carbon fi ltered' oifi The-carbomfilter cake is Washed with 140 parts by'volume of dilute hydrochloric abidoffpl-I 1 and thesewvashings combined with the filtratei the resulting solution beingadj'ustedto -pII- '11 by the addition of aqueous sodium hydroxide' and then shaken successively with threeportions:

1 each parts by volume, of butyl acetate? thebutyl acetate extracts being separatd and bulked. This extract is reextracted' with 50pa'rts' by volume of water at pH 2} the aqueous-extract separated and the pH adjusted td'lliby the-ad" dition" of aqueous sodium hydroxide 8;8-"part's by Weight of procaine base are precipitatedin" a purity of 99.2% by weight, representing, an overall yield of 89 Example 2 5,000 'parts byivolume of procaine containing liquorsaretreated with 2G %--by=weight aqueous sodium hydroxide-to" adjust thepH' ofthsoluf' tion to 7 -8, and50 parts by weight 'offi'nel'y* groundactivated carbon areadded' thereto-j the 4 volume of 1.0 N hydrochloric acid and these washings added to the filtrate. 300 parts by volume of butyl acetate are added to the bulked solution and 20% by weight aqueous sodium hydroxideadded to the mixture with stirring in amount' such that the-solution is finally of pH 11. The solvent and aqueous layers are separated and the aqueous phase further extracted with two 300 parts by volume portions of butyl acetate. The butyl acetate extracts obtained are bulked; made-extracted with three 150 parts by volume p'ortions of water at an equilibrium pH of-2-255 obt'airie y the addition of hydrochloric acid? Finally? theaqueous extracts thus obtaified' are-"combined and 20% by weight aqueous sodiumhydroxide'added slowly thereto with stirring-until preeipitation of the procaine base just commences, whereupon crystallisation thereof is in'du'ced'by seeding, followed by the further slow addition of the aqueous sodium hydroxide to a fir'ial- -p I-I Of 10.5'. Tl'i 'preoipitated "procaine base is --separated by= filtration, washed and dried giv ing an 87% recovery of white procaine baseof 50oparts by volumefof' an aqueous solutionof'f procaine-" of' a pH'dl'f-th'e range-2-3; containing 9:.75 'p'art's by} weight of procaine are treated with 1% "by-weight of a'ctivatedcarbon with agitation for'h'alf an liouran'dthe carbon filteredoff. The carbon filter cake is washed 'with' l l'il 'partsby volume of dilute sulphuricfacidfof pH land these washings" being combined with the filtrate, the

resulting-solution adjusted to pl-T- 11 by the add;-

tiono'f aqueous sodium hydroxide'an'd then shaken successively with three portions, each 50 parts by volume; of butyl acetate; the butyl acetate ex tracts-being separated andbulk'ed. This extract is-re-extracted with 50 parts by volume of Water atI-pHfZZ' the aqueous extractseparated and thepH a'dju'Sted' to 11' by theaddition of sodium hydroxid? SIB' p'artsby weight offprocaineb'ase are precipitated'in a purity "of 97.5% by weight representingari overall yield of =87 Example: 4-"- 56(l partsby volume of an aqueous solution'of procaine of a pH 'in'the range of 7-8, containing.

parts 'byweight'of procaine are treatedjwith 1%b3 weightof activated'carbon with agitation forhalf an hour to an'hour and the carbon" filtered off: The'carbon' filter cake is 'wa'shed' wi'th p'artsby volume of dilute sulphuric acid'of p 1 nd hes wa h ngs combined with. them-'- ti atei combined'solution is adjusted to pH 10.5 by the addition of aqueous sodium hydroxide and '8'."6-"partsby weight-of "procaine base of purity" comprises-contacting an aqueous solution of procai-n'e -at'a pil -less than about8 with activated carbon; separating the "aqueous solution, washing; the-"activated carbon with an aqueous dilute acid of normality not greate'rthian about "2 and therew l V c after 'adjustin'gjthe" pH [ofthe-carbon treated carbon' filter cake is washed wit-M15 parts-b9 aqueoussolution'-'-and thecarb'o'rr' washings to a" value greater than 8 and recovering the precipitated procaine base.

2. A process as claimed in claim 1, wherein the aqueous solution of procaine is agitated with activated carbon in amount about 1% by weight of the solution.

3. A process as claimed in claim 1, wherein the aqueous solution of procaine is passed through a static mass of activated carbon.

4. A process as claimed in claim 1, wherein the activated carbon is washed with an aqueous acid selected from the group consisting of hydrochloric acid and sulphuric acid.

5. A process as claimed in claim 1, wherein the pH of the carbon treated aqueous solution and the carbon washings is adjusted to a pH in the range 10-12.

6. A process for the recovery of procaine which comprises contacting an aqueous solution of procaine at a pH less than 8 with activated carbon, separating the aqueous solution, washing the activated carbon with an aqueous dilute acid of normality not greater than about 2, extracting the procaine from the carbon-treated aqueous solution and the carbon washings after adjustment of the pH to a value in excess of 8 with a substantially water-immiscible organic solvent for procaine base, re-extracting said organic solvent extract with water at a pH less than 6, separating the aqueous re-extract, adjusting the pH to a value greater than 8 and recovering the precipitated procaine base. 7

JOHN TALBOT McCOMBIE.

PAUL FREDERICK ERNEST MANN.

ANTHONY MUSGRAVE WILD.

No references cited. 

1. A PROCESS FOR THE RECOVERY OF PROCAINE WHICH COMPRISES CONTACTING AN AQUEOUS SOLUTION OF PROCAINE AT A PH LESS THAN ABOUT 8 WITH ACTIVATED CARBON, SEPARATING THE AQUEOUS SOLUTION, WASHING THE ACTIVATED CARBON WITH AN AQUEOUS DILUTE ACID OF NORMALITY NOT GREATER THAN ABOUT 2 AND THEREAFTER ADJUSTING THE PH OF THE CARBON TREATED AQUEOUS SOLUTION AND THE CARBON WASHINGS TO A VALUE GREATER THAN 8 AND RECOVERING THE PRECIPITATED PROCAINE BASE. 